A Mouse Model for Mental Disorders and Epilepsy

Case ID:

2010-021*-la

Web Published:

1/9/2013

Description:

Current
State of the Art

The Neuregulin/ErbB4 signaling pathway is involved in GABAergic
neurotransmission, an important inhibitory neurotransmission that regulates
several processes in the central nervous system including muscle tone. Aberrant
GABAergic function has been implicated in Schizophrenia, Schizo-affective
disorder and in Epilepsy. Clinically overlap has been observed in the
development of Schizophrenia, Schizo-affective Disorder and Epilepsy. In some
cases treatments for one disorder can cause symptoms of the other. This implies
common pathways intertwine in the development of these diseases, implying that
therapies can be designed to treat one or all disease states. Further, the
Neuregulin/ErbB4 pathway is dependent on down-regulation of AMPA signaling, an
anti-epileptic target, to function properly.

Schizophrenia affects ~ 1.1% of the adult population in the U.S.
The global schizophrenia market was valued at $15.9 billion in 2008 which is
expected to reach $17.2 billion by 2015. Therapeutics for patients suffering
from Schizophrenia include Fanapt (iloperidone) from Novartis and Zyprexia
Relprevv (olanzapine) from Eli Lilly.

Disadvantages
with the Current Art

Mouse models available for studies in Schizophrenia,
Schizo-affective disorder and Epilepsy include those that manipulate specific
candidate genes, those thought to be causative of the disorder. In some cases
these models only reveal discreet parts of the disease etiology or progression
and do not represent the entirety of the symptoms. The most useful appear to be
those that chemically and/or surgically manipulate the animal model to mimic the
disorders. Although fruitful for therapeutic discoveries these cannot always be
used to identify therapeutics that can treat a patient with an underlying
genetic disorder.

Advantages
of the Invention

Dr. Lin Mei and co-workers have developed a mouse model system
where Neuregulin1/ErbB4 function is disrupted specifically in
parvalbumin-positive synapses. PV-positive cells represent GABAergic
interneurons responsible for the neurological output of pyramidal cells.
Pyramidal neurons are the primary and most numerous excitation units of the
mammalian prefrontal cortex and the corticospinal
tract. This suggests that pyramidal cells
play important roles in advanced cognitive functions and muscle tone. Mice in
this model system displayed symptoms of hyperactivity, impaired working memory
and deficits in prepulse inhibition, similar to other models for Schizophrenia.